The long-term objective of this grant has been the development of effective therapeutic vaccines against malignant melanoma. Project III's is the evaluation of a living irradiated polyvalent melanoma cell vaccine (PMCV). This project has four Specific Aims: 1. We will conduct a multicenter randomized Phase III trial of PMCV as a postsurgical adjuvant immunotherapy in AJCC Stage III melanoma. The control arm will be interferon alpha 2b (IFNalpha-2b), which has recently been approved by the FDA. Because PMCV has a much lower toxicity profile than IFNalpha-2b, the vaccine would be the preferred adjuvant if its clinical efficacy proves comparable to that of IFNalpha-2b. 2. To determine whether new immunological and molecular markers can be used to detect subclinical metastatic melanoma an quantitate the response to adjuvant therapy. We hypothesize that these new techniques can be used as stratification factors in predicting the outcome of adjuvant therapy for melanoma patients who have no clinical evidence of disease following surgery. 3. Determine the immune response that optimally impacts the clinical outcome of PMCV recipients enrolled in the Phase III trial. Our goal is to develop an immune response model that can serve as a prototype for monitoring vaccine therapy in patients with melanoma. 4. Conduct a series of pilot studies (Phase I/II) to determine whether the immune response against tumor-associated antigens can be enhanced by combining PMCV immunotherapy with cytokines that have activity in melanoma (e.g., IFNalpha-2b) or agents that are effective adjuvants for inducing tumor rejection responses in animal models.